The present invention is directed at an improved method for dehalogenating halogen-containing compounds, particularly substituted alkylheteroaryl halo-compounds. More specifically, the present invention is directed at dehalogenating 4-(2 amino-3-chloropropyl) imidazole to produce .alpha.-methyl histamine.
Optically pure (R)-(-)-.alpha.-methyl histamine, ##STR3## has been found to selectively agonize histamine H.sub.3 receptors. See for example, The Journal of Medicinal Chemistry Vol. 33, No. 1 pages 4-11 (1990), and Nature Vol. 327 pages 117-123 (May, 1987). However, preparation of the desired optically active compound has been difficult and relatively expensive. European Journal of Medicinal Chemistry, Volume 24, pages 259-262 (1989) describes a process for preparing (R)- and (S)-.alpha.-methylhistamine from (R) and (S)-histidinol which included chlorination by SOCl.sub.2 followed by reduction of the chloromethyl substituent with H.sub.2 -Pd/C. However, the reduction of the chloromethyl substituent has to be conducted under relatively high pressure (25-34 atmospheres) and a hydrogen atmosphere.
Ison and Casy in Journal of Medicinal Chemistry, Volume 13 No. 5, page 1027, (1970) describe a method for the production of .alpha.-methylhistamine from the dihydrobromide salt in a heated pressure vessel. However, the use of a high pressure halide reduction is not desirable because of the increased cost and safety considerations.
Ram and Ehrenkaufer in Synthesis, pages 91-95, (February, 1988) describe the dehalogenation of 2,4,6-trichlorophenol to phenol using ammonium formate in the presence of methanol and a palladium-on-carbon catalyst. Anwer and Spatola in Tetrahedron Letters, Vol. 26 No. 11, pp 1381-1384 (1985) also describe a similar method for the dehalogenation of 2,4,6-trichlorophenols.
In Synthesis, pages 929-932, (November, 1980) Anwer and Spatola describe a method to produce leucine-enkephalin by the rapid removal of hydrogenolysable protecting groups, such as benzyloxycarbonyl, at room temperature and under atmospheric pressure using ammonium formate and a Pd/C catalyst.
Johnston and Wilby in Chem. Rev. Vol. 85, pages 129-170, (1985) describe a method for heterogeneous transfer hydrogenolysis of aromatic halides using triethylammonium formate in the presence of 5% Pd/C catalyst. Table XXX shows the removal of halogen from substituted benzenes where the halogen was bonded directly to the ring or to an alkenyl substituent. There were no examples illustrating the removal of halogen from an alkyl substituent and, in particular removal of only a single halogen.
Accordingly, it would be advantageous to have a method for dehalogenating halo-containing compounds, particularly monohaloalkylheteroaryl compounds substantially completely under relatively mild conditions without significantly affecting the stereoconfiguration.
The present invention is directed at a method for dehalogenating a compound of the generalized structure ##STR4## wherein R.sub.1, R.sub.2 and R.sub.3 independently are hydrogen or methyl, or R.sub.1 and R.sub.3 taken together represent a methylene, with the proviso that R.sub.1, R.sub.2, and R.sub.3 are not all methyl;
X is halogen; PA1 m is zero, 1 or 2; and PA1 Y is a pharmaceutically acceptable acid, PA1 comprising contacting the compound with a catalytic hydrogenolysis system to produce a compound of the structure ##STR5##
The catalytic hydrogenolysis system preferably comprises:
A. a palladium or nickel hydrogenolysis catalyst preferably supported and more preferably selected from the group consisting of Pd/C and Pd (OAc).sub.2 /C; and PA0 B. a hydrogen donor selected from the group consisting of unsaturated hydrocarbons having up to 10 carbon atoms, primary and secondary C.sub.1 -C.sub.8 alcohols, C.sub.1 -C.sub.10 primary and secondary alkyl and aryl amines, phosphorus-containing acids, C.sub.1 -C.sub.3 organic acids, and salts of the phosphoric and organic acids. PA0 A. Pd/C; and PA0 B. a hydrogen donor selected from the group consisting of cyclohexene, cyclohexediene, phosphinic acid, sodium phosphinate, triethylammonium formate, ammonium formate, and tetralin, more preferably ammonium formate. PA0 A. About 25 to about 600 wt % hydrogenolysis catalyst, preferably about 75 to about 150 wt %; PA0 B. About 60 to about 850 wt % preferably about 150 to about 250 wt % hydrogen donor; and, PA0 C. About 800 to about 4000 wt % solvent, preferably about 1500 to about 2100 wt %.
A particularly preferred catalytic hydrogenolysis system comprises:
A solvent optionally may be present in the hydrogenolysis catalyst system. The solvent preferably comprises C.sub.1 -C.sub.4 aliphatic alcohols, dimethyl formamide or formic acid with methanol being particularly preferred.
The halogen substituent preferably is chlorine, and substituents R.sub.1, R.sub.2 and R.sub.3 preferably are hydrogen. The compound which is dehalogenated preferably is optically active and more preferably has the (S)-configuration.
The hydrogenolysis preferably is conducted at up to 100.degree. C. and atmospheric pressure.
The present invention also is directed at a method for preparing a pharmaceutical composition comprising:
A. dehalogenating a compound of formula I with a catalytic hydrogenolysis system to produce a compound of formula II; and
B. admixing a pharmaceutically acceptable carrier with the compound of formula II.